Chagas disease (CHD) caused by Trypanosoma cruzi (T. cruzi) is endemic in Latin America and an emerging disease in the US and other developed countries. The overall prevalence of human T. cruzi infection is at ~16-18 million cases, and ~120 million people are at risk of infection. CHD is a complex disease with two clinically distinct phases: acute Chagas disease, which appears shortly after infection and lasts 4-8 weeks, and chronic Chagas disease, which develops from an asymptomatic indeterminate form to a chronic symptomatic phase 10-30 years later in about one-third of all cases. Immunopathology due to parasite persistence is considered a key element in the development of chagasic cardiomyopathy. The overall goal of these studies is to gain insight into how T. cruzi dysregulate macrophages to enhance its survival and whether activation of inflammasomes is useful in controlling parasite burden. Our hypothesis is that T. cruzi escapes macrophage-mediated clearance by a suboptimal activation of inflammasomes and IL-1 and the resultant parasite persistence establishes an atmosphere conducive to chronic disease. We propose that parasite molecules (e.g. kinetoplast (kDNA)) and host molecules (i.e. mitochondrial DNA (mtDNA)) are released during infection and provide a signal for the activation of inflammasomes in macrophages. This study will also focus on the role of host cell mtDNA (DAMPs) and kDNA (PAMPs) of T. cruzi in inflammasome activation to gain an insight into the relative contribution of each during T. cruzi pathogenesis and the evolution of Chagasic cardiomyopathy. These hypotheses will be examined by two specific aims: AIM 1: To test the hypothesis that T. cruzi infection of macrophages results in suboptimal ROS dependent inflammasome activation and IL-1 production, and contributes to parasite survival. Aim 2: To test the hypothesis that T. cruzi kinetoplast DNA (kDNA) and host mitochondrial DNA (mtDNA) direct inflammasome activation in macrophages. Our results will pave the way for designing therapeutic interventions against this debilitating disease.